Editorials
High-Sensitivity C-Reactive Protein and Bleeding Events in Atrial Fibrillation Patients Treated With Direct Oral Anticoagulants
2020 Volume 84 Issue 3 Pages 376-377
Details
2020 Volume 84 Issue 3 Pages 376-377
Atrial fibrillation (AF) often causes ischemic stroke by forming a thrombus in the left atrial appendage.1 Recently, direct oral anticoagulants (DOACs) such as thrombin inhibitors and factor activator-X (FXa) inhibitors have become widely used instead of warfarin. DOACs have been shown in several studies to be non-inferior compared with warfarin in preventing thromboembolic events and to be superior in reducing bleeding events.2–4 However, even in patients treated with a DOAC, serious bleeding events can still occur. Therefore, each DOAC should be carefully used in AF patients after evaluating the balance between reducing effects on ischemic stroke and increasing effects on serious bleeding events. Various risk stratification scores have been developed to identify patients at risk of stroke and bleeding, which are used practically in the clinical setting.5 Among those for bleeding risk assessment, the HAS-BLED6 and ORBIT7 scores are famous and are frequently used by many physicians. In recent years, it is notable that several biomarkers have emerged to provide incremental information on the risk of bleeding in patients with AF. For instance, Hijazi et al proposed that the ABC-bleeding score, in which plasma concentrations of 3 biomarkers, including growth differentiation factor-15 (GDF-15), high-sensitivity cardiac troponin T (cTnT-hs) and hemoglobin, are measured, may be better than the HAS-BLED and ORBIT scores.8 However, these biomarkers are non-specific and have large intra-individual variability. Biomarkers that correctly reflect systemic inflammation are C-reactive protein (CRP) and interleukin-6 (IL-6). In fact, the plasma levels of CRP and IL-6 are associated with bleeding events in AF patients.9,10 Because CRP and IL-6 are commonly evaluated in the clinical setting, it would be interesting to know whether they can provide incremental information to assess bleeding risk in patients with AF.
Article p 411
In this issue of the Journal, Hamanaka et al11 report on the effect of systemic inflammation on bleeding risk in AF patients treated with DOACs. They conducted a single-center prospective registry of 2,216 nonvalvular AF patients treated with DOACs. The high-sensitivity CRP (hsCRP) was measured within 3 months before (pre-hsCRP) and 6±3 months after initiation of DOAC therapy (post-hsCRP). The post-hsCRP value was associated with major bleeding, whereas the pre-hsCRP was not. Patients with a post-hsCRP >0.100 mg/dL more frequently experienced major bleeding than those with ≤0.100 mg/dL. Based on these findings, Hamanaka et al proposed the “ORBIT-i score”, a newly modified ORBIT score, as a novel score to reflect the bleeding risk associated with systemic inflammatory status (Table). Because the ORBIT-i score showed a higher C-index of 0.672 (95% confidence interval [0.612–0.732]) compared with the ORBIT and HAS-BLED scores, Hamanaka et al concluded that the ORBIT-i score had higher discriminative performance in comparison with the conventional bleeding risk scores. More interestingly, they demonstrated that hsCRP significantly decreased after the start of DOAC prescription (pre0median 0.08 interquartile range [0.04–0.17] mg/dL vs. post 0.06 [0.03–0.13] mg/dL, P<0.001). The significant reduction in hsCRP was consistent across all DOACs. The results suggested that DOACs may reduce bleeding events by attenuating systemic inflammation. Although the detailed mechanism by which DOACs reduced hsCRP remains unclear in the study,8 the following could be candidates (Figure). Dabigatran, an oral direct thrombin inhibitor, has been shown to improve endothelial function and reduce oxidative stress.12 On the other hand, FXa stimulates protease-activated receptor 2 (PAR-2). As the activation of PAR-2 promotes pro-inflammatory activation of macrophages,13 anti-FXa drugs may suppress PAR-2-mediated inflammation. In fact, we recently demonstrated that cardiac PAR-2 upregulation and macrophage infiltration were evident in transverse aortic constriction (TAC)-treated rats, both of which were attenuated by the treatment with rivaroxaban.14
| Score | Factors |
|---|---|
| HAS-BLED Score6 | Age >65 years, hypertension, renal disease, liver disease, stroke history, prior major bleeding or predisposition to bleeding, labile INR, medication usage predisposing to bleeding, alcohol use |
| ORBIT score7 | Age >65 years, reduced hemoglobin/hematocrit/history of anemia, bleeding history, insufficient kidney function, treatment with antiplatelet drug |
| ABC-bleeding score8 | Age, history of bleeding, 3 biomarkers (hemoglobin, cTnT-hs, and GDF-15 or cystatin C/CKD-EPI) |
| ORBIT-i score11 | ORBIT score+inflammatory marker (post-hsCRP) |
CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration; cTnT-hs, high-sensitivity cardiac troponin; GDF-15, growth differentiation factor 15; hsCRP, high-sensitivity C-reactive protein; INR, international normalized ratio.
Possible mechanisms for reduction of bleeding events in patients with atrial fibrillation (AF) treated with direct oral anticoagulants (DOACs). hsCRP, high-sensitivity C-reactive protein; PAR-2, protease-activated receptor 2.
Again, it is very important to assess the bleeding risk in patients treated with DOACs. A fascinating model, the ORBIT-i score, has been introduced in this issue of the Circulation Journal and its usefulness should be evaluated in a large-scale study in the future.
None.
N.T. is a member of Circulation Journal ’ Editorial Team.
